European Journal of Cardiovascular Medicine

Urticaria is defined as a disease that may present with short lived itchy weals, angioedema or both [1]. Chronic urticaria (CU) is defined as urticaria persisting daily or almost daily for more than 6 weeks [2]. The exact prevalence of CU is unknown. About 0.1–3% of the population are affected by this condition [3]. There are two further types of chronic urticaria: chronic spontaneous (also called chronic idiopathic) and chronic-induced urticaria. The latter is seen in younger adults and is associated with underlying stimuli such as temperature (heat or cold), pressure, vibration, and solar due to ultraviolet A (UVA) or visible light [4]. CSU can be linked to various autoimmune conditions, such as thyroid disorders, vitiligo, rheumatoid arthritis, and pernicious anemia. It also has a considerable impact on the patient's quality of life.

CIU is often difficult to manage. Guidelines recommend initiating treatment with second-generation, non-sedating H1-antihistamines, supported by evidence from double-blind clinical trials [5]. If symptoms persist, the dose may be increased, and a leukotriene receptor antagonist can be added. For patients unresponsive to these measures, second-line therapies are considered based on efficacy, cost, and safety. Omalizumab is highly effective but costly, while cyclosporine offers a more affordable alternative for antihistamine-refractory cases. Other alternatives include methotrexate, dapsone, and autologous serum therapy .  Long-term corticosteroids are not given in chronic urticaria due to their adverse effects [6].

Chronic urticaria (CU) is difficult to treat due to its unpredictable nature and poor response to standard therapies, often leading to patient frustration and poor compliance . This study explores the effectiveness of histaglobulin—a combination of histamine and human immunoglobulin—in providing symptom relief and targeting the underlying disease process.. Histaglobulin has been in use for a few decades in patient’s refractory to all other treatments of CIU [7]. It stimulates antibody formation to histamine that offers protection for six to 18 months against histamine released endogenously [8]. This immunotherapy has been suggested to be more effective than AST[9] . The study also compared the response to histaglobulin between ASST-positive and ASST-negative CU patients.

A single centre, open label, non-randomised prospective clinical study was carried out in the Dermatology Venereology and Leprosy (DVL) Out Patient Department (OPD) in our institute from  after obtaining the approval from the Institutional Ethics Committee.

Inclusion criteria:

Patients of both genders diagnosed with CSU presenting to the OPD were enrolled in the study after obtaining informed consent. Diagnosis was established based on a history of daily or near-daily occurrence of widespread, pruritic wheals persisting for more than six weeks, with individual lesions resolving within 24 hours, and exclusion of physical urticaria.

Exclusion criteria:

Exclusion criteria included patients under 18 years, pregnant or breastfeeding women, those on long-term immunosuppressive therapy for chronic urticaria, patients with chronic inducible urticaria, and individuals with known hypersensitivity to any study medication.

Sample size:

Patients of chronic spontaneous urticaria presenting to outpatient department were enrolled in the study after excluding physical urticaria. On analysing the previous studies and the prevalence of chronic urticaria we chose the sample size.

Baseline Evaluation:

After obtaining informed consent, all patients underwent a thorough baseline evaluation. This included a detailed clinical history documenting lesion duration, severity, diurnal variation, presence of angioedema, systemic comorbidities (such as thyroid disease, diabetes mellitus, and hypertension), concomitant medications, and any indications of physical urticaria or urticarial vasculitis. Female patients were assessed for pregnancy or lactation status. The baseline Urticaria Activity Score (UAS) was calculated, and data on the type and quantity of oral antihistamines used in the previous week were recorded. Routine laboratory tests comprised complete blood count with differential, urinalysis, stool examination for ova and cysts, thyroid function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and renal and liver function panels. An autologous serum skin test (ASST) was conducted following established guidelines[10], with patients subsequently categorized as ASST-positive or ASST-negative.

Treatment schedule and follow up:

Patients were administered weekly subcutaneous injections of 1 mL histaglobulin (HISTOGLOB®), manufactured by Bharat Serums and Vaccines Ltd., Maharashtra, India. Each injection contained 12 mg of human normal immunoglobulin and 0.15 mcg of histamine dihydrochloride and was given over a period of eight weeks. Cetirizine 10 mg tablets were prescribed as rescue therapy, to be taken as needed without exceeding the recommended daily dose. Weekly evaluations of treatment efficacy were conducted using the UAS, with the concluding assessment performed at 24 weeks.

Urticaria Activity score:

The Urticaria Activity Score (UAS) is a recognized instrument for evaluating disease severity in patients with chronic spontaneous urticaria (CSU). It measures two key symptoms: the quantity of hives and the intensity of itching. Each symptom is rated on a scale from 0 (none) to 3 (severe), resulting in a daily combined score from 0 to 6. The UAS7 is calculated by adding the daily scores over seven days, producing a weekly total between 0 and 42, where higher scores reflect more active disease. Throughout the eight-week course of subcutaneous injections, patients underwent weekly assessments using the UAS. Following the treatment period, patients were instructed to return to the outpatient department if symptoms recurred. Additionally, a follow-up evaluation was performed at 24 weeks to determine the disease status.

This study evaluated the chronic urticaria patients and assessed the clinical outcome of patients on injection histaglobulin. After the data analysis during this study period, 66 patients with chronic urticaria were diagnosed. Out of 66 patients a total of 28 patients who completed all 8 weeks of treatment were considered as study participants in this study. Those chronic urticaria patients who withdrawal from the study or failure to take complete treatment were excluded from this study.

The mean±SD age in the years of study population is 38.2±9.7. Male population presented chronic urticaria were 57.1% (16 out of 28) and female population was 42.8%, with the male to female ratio of 1.3:1. The mean duration of the disease is 18.2±15.3 months. The autologous serum skin test (ASST) was positive in 13 (46.4%) patients and negative in 15 (53.5%) patients. Urticaria Activity score has been reduced drastically after the completion of treatment which was statistically highly significant (Table 1).

Table 1. Observations in study population

Excellent response (>75% reduction) was observed in 19 patients; good response (51–75% reduction) in 3 patients; moderate response (25–50% reduction) in 5 patients; and poor response (<25% reduction) in one patient. By 24 weeks of starting the therapy, 25 patients (89.2%) had attained complete remission. Remaining two patients had taken at least 4 weekly injections continuously.

Urticaria Activity Score (UAS) baselines at the start of the treatment was 19.6±5.4. This basal UAS was gradually decreased to 3.9±5.5 after the completion of 8 weeks of treatment. The baseline of UAS noted after 24 weeks of completion of treatment was 3.5±4.2 (Table 2).

Table 2. UAS score based on the treatment cycles

Chronic urticaria is a common and debilitating skin disease characterized by hives, wheals and/or angioedema lasting 6 weeks or more. It can be a spontaneous where the clinical manifestations occur in the absence of specific triggers which is considered as chronic spontaneous urticaria and the other way of presentation is a chronic inducible urticaria, it is inducible symptoms which are elicited by specific stimuli [11]. Clinical manifestations of chronic urticaria appears due to the efficient function by a cell in normal component of the immune system i.e, mast cell or mastocyte which resides in the connective tissue, gets activated by invaders such as microorganisms, allergens or chemicals and release various inflammatory markers. The mast cells are considered to be the major effector cell in the pathophysiology of urticaria. Mast cells releases histamine and other mediators responsible for formation of wheal, angioedema and urticaria [12]. Activation of H₁ receptors in the skin induces itching, flare, erythema, whealing and contraction of smooth muscle in respiratory and gastro-intestinal tract. Activation of H₂ receptors contributes to erythema and whealing in the skin. In few patients autoantibodies against the high affinity IgE receptor (FcɛR1) or against IgE itself, indicating an autoimmune component [13].

Knowing the cause of chronic urticaria is difficult, there have been different etiologies such as infections, medications, food, insect bites, autoimmune, and malignancy. Management guidelines for chronic urticaria were published in 2022 and then necessary changes were met. The international guideline treatment algorithm recommends first-line second-generation antihistamines, with dosage ranging from the approved dose to four-fold up-dosing (off-label), followed by omalizumab (monoclonal anti-IgE) and ciclosporin (immunosuppressive) [11,14]. Few guidelines recommend montelukast before omalizumab [14]. If any underlying disease is present then treatment of it is indicated.

The mean±SD age in the years of study population is 38.2±9.7. Male population presented chronic urticaria were 57.1% (16 out of 28) and female population was 42.8%, with the male to female ratio of 1.3:1. The mean duration of the disease is 18.2±15.3 months. The autologous serum skin test (ASST) was positive in 13 (46.4%) patients and negative in 15 (53.5%) patients. Urticaria Activity score has been reduced drastically after the completion of treatment which was statistically highly significant. Usha NK et al [15] did a similar clinical scoring as our study they noted the mean duration of the urticaria is 18 weeks, ASST positive in 72% of patients and male population were predominantly notified. The Mean UAS 7 value reduced significantly by 8 weeks (p<0.05) and mean UAS 7 value at 24 weeks was (2.8±2.01). Thota S et al [16] reported 20 out of 35 patients were ASST positive, the mean USA at baseline is 5.7 and at the end of study is 1.01 i.e., the reduction accounts for 80%. Rajesh et al [17] noted the mean basal UAS was 18.9 ± 6.3 and by 24 weeks of starting the therapy, 23 patients (45%) had attained complete remission. Godse K et al [18] did a single centre study on chronic uriticaria management with histaglobin observed the mean age of study population as 36.8(±10.18) years and noticed 23 male and 15 female population out of 38 study subjects. They also concluded statistical significant reduction in mean UAS7 from Day 0 to Day 28.

By 24 weeks of starting the therapy, 25 patients (89.2%) had attained complete remission. Remaining two patients had taken at least 4 weekly injections continuously. Histaglobulin Injection is a medicine used to prevent various allergic conditions such as allergic rhinitis, eczema, urticaria, and generalized skin allergies [18]. Guchsin IS et al [19] used Histaglobulin in chronic urticaria patients with allergic rhinitis and concluded it is effective. Rudzki et al [20] was the first study used against CU along with prurigo. Histaglobulin Injection is well tolerated and does not usually cause any common side effects. It is a sterile preparation of histamine dihydrochloride coupled to active protein fraction extracted from human blood (gamma globulin). Histaglobulin decreases IgE levels and increase the serum binding capacity of histamine which will help to improve the clinical efficacy and quality of life [21]. Histaglobulin injections frequency and duration is varied in different studies. For instance, Usha NK et al [15] was administered weekly injections for 8 weeks in line with the present study. Godse K et al [18] and Gushchin IS et al [19] gave 3 subcutaneous histaglobulin injections on each, on day 0, 7, and 14.

Urticaria Activity Score (UAS) baselines at the start of the treatment was 19.6±5.4. This basal UAS was gradually decreased to 3.9±5.5 after the completion of 8 weeks of treatment. The baseline of UAS noted after 24 weeks of completion of treatment was 3.5±4.2. Godse K et al [18] study gave injections of Histaglobulin on Day 0,7 and 14, noted the improvement in UAS7 was seen in 91.89% patients with 35.14% patients showing complete improvement (UAS 7 ‘zero’) at the end of treatment. Gushchin IS et al [19] reported improvement in chronic urticaria in 82.5% patients and compete improvement in 15% patients with Histaglobin. In similar to our study Godse K et al [108] and Gushchin IS et al [19] reported the higher rate of improvement with Histaglobulin, whereas Rudzki et al [20] and Rajesh et al [17] observed 10.8% and 48.3% respectively. In the present study we observed 82.6% of reduction in UAS among chronic urticaria patients with Histaglobin injections, on analysis of reduction rate after weeks of treatment rajesh et al showed 80.4%.

Further studies on Histaglobulin mode of action, its pharmacodynamics in human body and maintaining the levels of antibodies to achieve the complete resolution of symptoms and to prevent the recurrences is much needed. Few studies suggested repeated six monthly injections of Histaglobulin to maintain the antibody titres [22,23]. Further studies on regulation of eosinophils and its function and the maintainance of antibodies by giving histamine and mouse gamma globulin is undergoing [24].

Patients with chronic urticaria administered with weekly injections of Histaglobulin showed significant improvement in symptoms during the treatment period irrespective of ASST status. and a good percentage of people had complete remission from chronic urticaria. Histaglobulin is a effective drug to manage chronic urticaria. Histaglobulin is a safe, well-tolerable and less or no adverse side effects drug which can be considered as a best adjunt to other alternative medications in the management of chronic urticaria.

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